DOSE INTENSIFICATION BY GENE TRANSDUCTION IN CANCER

该计划的总体目标是研究DNA修复的作用 在化疗耐药性，特别是对DNA损伤的耐药性方面， 剂.在每个项目中，研究人员将寻求利用分子 技术，以研究DNA修复蛋白的关系， 表达对细胞对烷化剂和化疗的抗性- 诱导氧化损伤，或影响细胞对化疗的抗性 在临床前或临床研究中。具体目标包括： 脑肿瘤、淋巴瘤、儿童实体瘤的治疗方法 肿瘤和癌前遗传病范可尼贫血 个别项目探索使用逆转录病毒载体和转基因 小鼠对氯乙基亚硝基脲（CENU）和其他 烷化剂，如链脲霉素、博来霉素和 环磷酰胺一项利用基因转移技术在 高风险脑肿瘤患者。另一种方法 增加治疗效果涉及选择性消耗 肿瘤细胞DNA修复能力，这是在这个建议中开发的， 临床前和临床研究。由于器官的毒性 使用CENUs和其他烷化剂的强化化疗是 骨髓和肺，该计划还探讨了DNA修复的作用， 这些器官中的蛋白质表达， 几种烷化剂的作用。此外，氧化性DNA损伤 由于化疗是研究利用细胞从病人范科尼 贫血作为一种模式拟议的研究计划借鉴了一组 经验丰富、资金充足的调查人员， DNA修复、造血、分子生物学、载体经验 技术、药理学和肺生物学。该计划旨在编织 将这些兴趣和专业知识整合到一个有凝聚力和相互关联的研究中， 一项能够产生治疗人类疾病的创新方法的计划 癌

The overall goal of this program is to investigate the role of DNA repair in chemotherapy resistance, particularly resistance to DNA damaging agents. In each project, investigators will seek to exploit molecular technology either to investigate the relationship of DNA repair protein expression to resistance of cells t alkylating agents and chemotherapy- induced oxidative damage, or to effect resistance in cells to chemotherapy in preclinical or clinical studies. Goals specifically include new approaches to the treatment of brain tumors, lymphomas, childhood solid tumors, and the pre-cancerous genetic condition, Fanconi Anemia. Individual projects explore the use of retroviral vectors and transgenic mice to effect resistance to chloroethylnitrosoureas (CENU) and other alkylating agents, such as, streptozotocin, bleomycin and cyclophosphamide. A clinical trial using gene transfer technology in patients with high risk brain tumors is proposed. An additional approach to increasing therapeutic effectiveness involves selective depletion of tumor cell DNA repair capacity, which is developed in this proposal in both pre-clinical and clinical studies. Since the organs of toxicity of intensive chemotherapy with both CENUs and other alkylating agents are the bone marrow and lung, the program also explores the role of DNA repair protein expression in these organs in protection from the cytotoxic actions of several alkylating agents. In addition, oxidative DNA damage due to chemotherapy is studied utilizing cells from patients with Fanconi Anemia as a model. The proposed research plan draws upon a group of experienced and well-funded investigators with diverse but complimentary experience in DNA repair, hematopoiesis, molecular biology, vector technology, pharmacology, and lung biology. The program seeks to weave these interests and expertise into a cohesive and interrelated research plan which can produce innovative approaches to the treatment of human cancer.